Lacosamide (Compound I) is the international commonly accepted name for (2R)-2-(acetylamino)-3-methoxy-N-(phenylmethyl)propanamide (which is also known as (R)-N-benzyl-2-acetamido-3-methoxypropionamide), and has an empirical formula of C13H18N2O3 and a molecular weight of 250.30 g/mol.

Lacosamide is an active substance indicated for adjunctive treatment of partial-onset seizures and diabetic neuropathic pain. In the United States, lacosamide is marketed under the name VIMPAT™ for the treatment of epilepsy.
Examples 1 and 2(b) of U.S. Pat. No. 5,773,475 disclose the isolation of lacosamide after evaporation from acetonitrile and filtration or trituration with diethyl ether. Lacosamide was obtained substantially enantiomerically pure, as defined therein, as was ascertained by the addition of excess (R)-(−)-mandelic acid to a CDCl3 solution of lacosamide, which gave only one signal for the acetyl methyl and ether methyl protons. In Example 5 of U.S. Pat. No. 5,773,475, lacosamide was prepared from D-serine and was purified by flash chromatography to obtain lacosamide as the (R)-enantiomer, but no mention was made regarding its enantiomeric purity. U.S. Pat. No. 5,773,475 generally indicates that the optical purity of lacosamide may be enhanced by further separation of the (S)-enantiomer from the (R)-enantiomer, by standard techniques known in the art, such as chiral chromatography using a standard chiral support known in the art. U.S. Pat. No. 5,773,475 further reports the melting point of the thus obtained solid lacosamide as 143-144° C. However, it does not report whether the solid is crystalline.
The continuation-in-part of U.S. Pat. Nos. 5,773,475, 6,048,899 discloses two examples for the preparation of lacosamide. Example 1 of U.S. Pat. No. 6,048,899 corresponds to Example 5 of parent U.S. Pat. No. 5,773,475. However, Example 1 of U.S. Pat. No. 6,048,899 indicates that lacosamide is obtained as an approximate 85:15 mixture of the (R)- and (S)-enantiomers respectively. In Example 2 of U.S. Pat. No. 6,048,899, lacosamide is obtained substantially enantiomerically pure, as defined therein, as was ascertained by the addition of excess (R)-(−)-mandelic acid to a CDCl3 solution of lacosamide. However, it does not report whether the solid is crystalline.
European Patent Application No. 1799635A1 relates to lacosamide preparation wherein the methylation step is carried out using dimethylsulphate and either n-butyl lithium or aqueous sodium hydroxide and phase transfer catalysis. EP 1799635A1 indicates that the removal of the (S)-enantiomer during production of lacosamide is extremely difficult. The methylation step using dimethylsulphate is described to be advantageous since it does not result in any racemization of the lacosamide product. However, the use of dimethylsulphate, which is a strong, highly toxic methylating agent, may lead to safety and environmental issues when producing lacosamide on a large scale. Furthermore, the use of n-butyl lithium at industrial scale is undesired since n-butane, a highly flammable gas, is obtained as a by-product of the reaction. On the other hand, phase transfer catalysts are expensive reagents which are difficult to be removed due to their high solubility in both water and organic solvents. Example 3 describes that the lacosamide product was crystallized by cooling a solution in ethyl acetate and the thus isolated lacosamide was obtained with a chiral purity of 99.8% e.e. However, EP 1799635A1 does not report any physical properties for the obtained lacosamide.
European Patent Application No. 2067765A2 relates to lacosamide preparation wherein N-trityl-D-serine is used as a starting material in order to minimize racemization due to the use of the trityl bulky protecting group, thus providing lacosamide substantially free of the (S)-enantiomer. However, such a process suffers from drawbacks, including for example the potential cost associated with the use of the above mentioned D-serine starting material and furthermore the N-protection/N-deprotection steps of the amine moiety also being potentially associated with cost and productivity issues for the overall process when used on an industrial scale. Concretely, the use of N-trityl protecting group is particularly detrimental due to the very low atom efficiency of this process, since the molecular weight of the N-trityl protecting group (243.33 g/mol) is comparable to the molecular weight of lacosamide (250.30 g/mol). EP 2067765A2 also specifically describes the isolation of lacosamide after evaporation from dichloromethane or ethyl acetate and reports a melting point of 142-143° C. and a chiral purity by HPLC between 99.98 and 100%. The isolated lacosamide is said to be recrystallized in toluene or ethyl acetate. However, EP 2067765A2 does not report physical properties for the obtained lacosamide.
PCT Patent Application No. WO 2010/052011 describes different processes for the manufacture of optically enriched lacosamide. One of the processes relates to the preparation of lacosamide as a mixture of enantiomers which is thereafter separated by chiral chromatographic separation into its different enantiomers. Another process relates to the resolution of the lacosamide intermediate 2-amino-N-benzyl-3-methoxypropionamide by diastereomeric salt formation or chiral chromatographic separation followed by acetylation and crystallization of the obtained lacosamide. However, such chiral chromatographic separation techniques are costly processes. Also resolution of an enantiomeric mixture by diastereomeric salt formation requires adequate chiral resolving agent available in an optically pure form, which can be both difficult and expensive, and furthermore requires recovery of the chiral resolving agent in high yield.
PCT Patent Application No. WO 2009/146325 describes polymorphic Forms I, II and III and an amorphous Form of lacosamide and processes for the preparation thereof. According to WO 2009/146325 the crude lacosamide used as starting material in the Examples is prepared by known methods such as those described in U.S. Pat. No. 6,048,899 and U.S. Patent Application No. 2008/0027137 (the latter is the U.S. equivalent to above discussed EP 1799635A1). No mention is made regarding the enantiomeric purity of lacosamide as prepared in accordance with WO 2009/146325.
PCT Patent Application No. WO 2010/060624 discloses polymorphic Forms R, S and T of lacosamide and processes for the preparation thereof. According to WO 2010/060624 the crude lacosamide used in the Examples as starting material is prepared by methods described in WO 97/033861, which is equivalent to above discussed U.S. Pat. Nos. 5,773,475 and 6,048,899. No mention is made regarding the enantiomeric purity of lacosamide as prepared in accordance with WO 2010/060624.
IPCOM 000187362D discloses a crystalline Form of lacosamide characterized by X-ray diffraction and prepared by recrystallization from 2-propanol at 50° C.
Polymorphism is defined as the ability of a substance to exist in two or more crystalline phases that have a different arrangement and/or conformation of the molecules in the crystal lattice. Polymorphs typically differ in their physical properties such as, for example, melting point, solubility, and chemical reactivity. Thus, the particular characteristics of the respective polymorphs can appreciably influence the solubility profile of a chemical substance, such as the dissolution rate. Further, the particular characteristics of the respective polymorphs can appreciably influence pharmaceutical properties such us dissolution rate and bioavailability.
Crystalline solids can often require a significant amount of energy for dissolution due to their highly organized lattice like structures. For example, the energy required for dissolution of a drug molecule from a crystal lattice can be much higher than the energy required for dissolution from an amorphous Form.
Amorphous Forms of drugs can exhibit different solubility properties compared to crystal Forms, and in some instances amorphous pharmaceuticals can be markedly more soluble than their crystalline counterparts [Hancock B. C., Pharm. Res., 17(4), 397 2000]. Additionally, amorphous drugs can exhibit different bioavailability patterns, as compared to their crystalline Form. For some therapeutic indications, a particular bioavailability pattern may be favored with respect to another. Therefore, it is often desirable to have amorphous Forms of drugs and processes for their preparation.
There is an ongoing need for new and improved polymorphic Forms of existing drug molecules for improved drug formulation. For example, new and improved polymorphic Forms having desirable bioavailability and/or improved stability, are continually being sought.
In view of the aforementioned, there is a desire to identify and isolate various solid Forms of lacosamide that can be desirable for pharmaceutical formulation. Further, there is a desire to have a reliable and cost efficient process for producing lacosamide in one or more of its solid Forms and also with desirable enantiomeric purity.